Non-viral siRNA delivery to T cells: Challenges and opportunities in cancer immunotherapy

Hoeck, Jelter Van; Braeckmans, Kevin; Smedt, Stefaan C. De; Raemdonck, Koen

doi:10.1016/j.biomaterials.2022.121510

Cited by 13 publications

(4 citation statements)

References 296 publications

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“…The lead structure 93-O17S has been reported to achieve 6.5% and 8.2% gene recombination in CD8-and CD4-positive mouse spleen T cells, respectively. 20 Moreover, Ma and colleagues developed an LNP based on neurotransmitterderived lipids (NT lipids) inspired by the neurotransmitters such as tryptamine derivatives that could permeate the blood-brain barrier (BBB), which successfully delivered proteins, nucleic acids, and small molecule agents to neuronal cells through the BBB, achieving efficient brain delivery. 21 Cheng et al report a selective ORgan targeting (SORT) approach that adds a fifth component to enable tissue-specific delivery of mRNAs.…”

Section: Lnp Systemmentioning

confidence: 99%

Nucleic acid drug and delivery techniques for disease therapy: Present situation and future prospect

Wang,

Tang,

Tao

et al. 2024

Interdisciplinary Medicine

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Over the two decades, RNA drugs have gradually made their way from bench to bed. Initially, RNA was not an ideal drug since RNA molecules degrade easily and have a relatively short half‐life in the circulation system. Nevertheless, the chemical modification extended the half‐life of RNA in recent years, which makes RNA drugs a new star in drug discovery industry. RNA molecules hold many properties that facilitate their application as therapeutic drugs. RNAs could fold to form complex conformations to bind to proteins, small molecules, or other nucleic acids, and some even form catalytic centers. Protein‐encoding RNAs are the carriers of genetic information from DNA to ribosomes, and various types of non‐coding RNAs cooperate in the transcription and translation of genetic information through various mechanisms. To date, three mainstream RNA therapies have drawn widespread attention: (1) messenger RNA that encodes therapeutic proteins or vaccine antigens; (2) small interfering RNA, microRNA (miRNA), antisense oligonucleotides that inhibit the activity of pathogenic RNAs; and (3) aptamers that regulate protein activity. Here, we summarized the current research and perspectives of RNA therapies, which may provide innovative highlights for cancer therapy.

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Section: Lnp Systemmentioning

confidence: 99%

Nucleic acid drug and delivery techniques for disease therapy: Present situation and future prospect

Wang,

Tang,

Tao

et al. 2024

Interdisciplinary Medicine

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“…To effectively silence genes in the body, appropriate vectors are required for the delivery of siRNA. The ideal carrier delivery system should allow the avoidance of siRNA degradation by serum nuclease, the delivery of siRNA to target cells with high specificity and efficiency, the extension of the in vivo half-life, an improved cell uptake, the avoidance of MPS clearance, and have good biocompatibility, biodegradability, and non-immunogenicity [ 11 ]. The in vivo delivery of siRNA requires overcoming blood, tissue, cellular, and intracellular barriers in order to reach the target site and exert gene silencing.…”

Section: Introductionmentioning

confidence: 99%

The Efficacy and Safety of Polyethylene Glycol Cholesterol- and Tocopherol Polyethylene Glycol 1000 Succinate-Modified Transforming Growth Factor β1 Small Interfering RNA Lipid Nanoparticles in the Treatment of Paclitaxel-Resistant Non-Small-Cell Lung Cancer

Zeng,

et al. 2024

Pharmaceutics

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The aim of this study was to explore the efficacy and safety of TGFβ1 siRNA lipid nanoparticles (LNPs) modified with different PEG derivatives (PEG5000 cholesterol, abbreviated as CE; tocopherol polyethylene glycol 1000 succinate, abbreviated as TPGS) in the treatment of paclitaxel-resistant non-small-cell lung cancer. Three kinds of TGFβ1 siRNA LNPs were prepared via microfluidics technology, using different PEG derivatives and dosages (CE1.5, CE2.5, TPGS2.5) as variables. Their particle size, zeta potential, contents, and encapsulation efficiencies were determined. The inhibition of TGFβ1 mRNA and protein expression and the effects of the three kinds of LNPs on the proliferation of paclitaxel-resistant non-small-cell lung cancer cells (A549/T cell) were characterized. The distributions of the three siRNA LNPs in nude mice bearing A549/T tumors, especially at the tumor site, were observed using in vivo mouse imaging technology, and their corresponding efficacies were evaluated. The average particle size of the three kinds of TGFβ1 siRNA LNPs was about 70–80 nm, and they were capable of charge flipping. All three siRNA LNPs could effectively inhibit the expression of TGFβ1 mRNA and protein in A549/T cells and inhibit the proliferation of A549/T cells in vitro. The results of in vivo mice imaging showed that the three kinds of siRNA LNPs, when labeled with cypate, retain strong fluorescence in the tumor at 24 h. The pharmacodynamic results, such as for relative tumor volumes and tumor inhibition rates, reveal that TGFβ1 siRNA LNPs modified with CE1.5, CE2.5, or TPGS2.5 can be used to effectively treat paclitaxel-resistant lung adenocarcinoma. The histopathological results showed that the three kinds of LNPs have a certain toxicity but are relatively safe compared to common forms of chemotherapy such as cabazitaxel. TGFβ1 siRNA LNPs modified with CE1.5, CE2.5, and TPGS2.5 can inhibit TGFβ1 mRNA and protein expression in A549/T cells in vitro and can accumulate and play a role in the tumor tissue of nude mice, features that can be exploited for treating paclitaxel-resistant lung adenocarcinoma.

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“…The siRNA therapeutics also present significant challenges, including safety and stability in vivo as well as the delivery of siRNA to the required cells and organs [ 38 , 39 , 40 ], which makes nanomaterial design more challenging. Therefore, the design of the vector should not only minimize harm to the human body but also facilitate the delivery of siRNA while overcoming the delivery challenges [ 41 ].…”

Section: Introductionmentioning

confidence: 99%

Research Status and Prospect of Non-Viral Vectors Based on siRNA: A Review

Tong

Liu

Cao

et al. 2023

IJMS

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Gene therapy has attracted much attention because of its unique mechanism of action, non-toxicity, and good tolerance, which can kill cancer cells without damaging healthy tissues. siRNA-based gene therapy can downregulate, enhance, or correct gene expression by introducing some nucleic acid into patient tissues. Routine treatment of hemophilia requires frequent intravenous injections of missing clotting protein. The high cost of combined therapy causes most patients to lack the best treatment resources. siRNA therapy has the potential of lasting treatment and even curing diseases. Compared with traditional surgery and chemotherapy, siRNA has fewer side effects and less damage to normal cells. The available therapies for degenerative diseases can only alleviate the symptoms of patients, while siRNA therapy drugs can upregulate gene expression, modify epigenetic changes, and stop the disease. In addition, siRNA also plays an important role in cardiovascular diseases, gastrointestinal diseases, and hepatitis B. However, free siRNA is easily degraded by nuclease and has a short half-life in the blood. Research has found that siRNA can be delivered to specific cells through appropriate vector selection and design to improve the therapeutic effect. The application of viral vectors is limited because of their high immunogenicity and low capacity, while non-viral vectors are widely used because of their low immunogenicity, low production cost, and high safety. This paper reviews the common non-viral vectors in recent years and introduces their advantages and disadvantages, as well as the latest application examples.

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Non-viral siRNA delivery to T cells: Challenges and opportunities in cancer immunotherapy

Cited by 13 publications

References 296 publications

Nucleic acid drug and delivery techniques for disease therapy: Present situation and future prospect

Nucleic acid drug and delivery techniques for disease therapy: Present situation and future prospect

The Efficacy and Safety of Polyethylene Glycol Cholesterol- and Tocopherol Polyethylene Glycol 1000 Succinate-Modified Transforming Growth Factor β1 Small Interfering RNA Lipid Nanoparticles in the Treatment of Paclitaxel-Resistant Non-Small-Cell Lung Cancer

Research Status and Prospect of Non-Viral Vectors Based on siRNA: A Review

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